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PCRI Insights February, 2005 vol. 8, no. 1
By Stanley A. Brosman, MD Pacific Urology Institute, Pacific Clinical Research, Santa Monica, CA

IT DOESN’T TAKE VERY LONG WHEN DISCUSSING TREATMENT OPTIONS FOR PROSTATE CANCER BEFORE WE REALIZE THAT WE DON’T HAVE THE ANSWERS TO MANY IMPORTANT QUESTIONS. Is this medication better than that one? How long is hormonal treatment necessary? Is surgery better than radiation therapy? Do seed implants work better than IMRT? The list of unanswered questions goes on because there is no way to answer them without a well-designed clinical trial.

At last year’s meeting of the American Urological Association, Howard Scher, the chief of Urologic Medical Oncology at Memorial Sloan-Kettering Cancer Center made a presentation specifically addressing the pressing need for well designed clinical trials. Clearly, this is an issue that needs to be seriously addressed or we will be asking the same questions regarding treatment when our grandchildren are diagnosed with prostate cancer.

There were 25 new agents presented at this meeting that have shown promise in (1) animal studies and (2) small numbers of men with all stages of prostate cancer, particularly those with androgen-independent disease. In order to design a study to compare each of these new agents against a placebo or another agent, 980 men would be needed for each new agent in order to detect a statistically and clinically meaningful difference between the two treatment groups. Since fewer than 5% of men currently participate in prostate cancer clinical trials, it will take years to learn if an agent is effective and so most of these agents will never get tested.

The Purpose of Clinical Trials
A clinical trial is designed to answer specific questions. There are three phases or types of clinical trials with several subdivisions for each. Phase I trials represent the first time that an agent has been tested in humans. These are usually performed with close monitoring in hospitals or specially designed Phase I centers. Usually small numbers of people (6-12) enter these trials. Toxicity and dosing are evaluated. Phase II trials usually involve 30-50 people. Once the dosing has been determined and the toxicity carefully evaluated, the test agent is ready for Phase III. Large numbers of individuals are necessary to compare the test agent to a placebo or another standard therapy. Of all the drugs that enter a clinical trial, only 5% successfully complete these trials and eventually enter the marketplace. This is one of the reasons our medicines cost so much.

Clinical trials are extremely complex and difficult to perform successfully. Relatively few physicians have been trained or have the interest in organizing and conducting these studies. To understand what is involved, I have designed a simplified hypothetical clinical trial that asks a specific question: How should men be managed who have a rising PSA following surgery? We will arbitrarily select two options, radiation therapy or hormonal therapy. This seems simple enough but let’s look at what is involved.

A Typical Clinical Trial
The Principal Investigator(s) who has conceived this clinical trial starts by writing a protocol that is a document detailing all aspects of the study. This includes instructions regarding how much and what type of radiation therapy, what type and doses of hormonal therapy, what tests would be needed, how often the patient should be seen, and how long a follow-up period is necessary to answer the question. The protocol stipulates who is eligible to participate and who is ineligible. For example, the protocol might stipulate that only men diagnosed with prostate cancer who have had surgery would be eligible, but those who had prior radiation therapy as treatment for their disease would be ineligible. Ordinarily, a protocol will have a list of 10-12 entry (or inclusionary) criteria and a similar number of exclusionary criteria.

The protocol is given to a bio-statistician who determines the number of men who would be needed to answer this question, or in the parlance of the statistician, what numbers are necessary to adequately power the study. To complicate matters, the two groups need to be balanced or stratified according to stage, grade, PSA, age, time between surgery and a rising PSA and any other factors that might affect the study. In order to deal with all of these factors, the bio-statistician determines that 1800 men are needed to enroll (900 in each arm) in this study in order to adequately power the study so that our question can be answered. An underpowered study ends up with either no answer or an inadequate answer. Time and money are lost and another study would need to be done.

A consent form describing the study is written according to Federal regulations. This is a lengthy and often complex document. The final protocol and the consent form are submitted for review and approval by an Institutional Review Board (IRB). Revisions are often requested by the IRB, and the documents are re-submitted. Each subject participating in the study must sign the approved consent form before entering the study.

A single institution would not be able to enroll this number of men. Additional investigators are needed, and they would be recruited from a large number of sites. If each site enrolled 50 subjects over a 3-4 year period, 36 sites would be needed. This is a massive undertaking to answer what seemed to be a straightforward question.

Significant Time and Money
The Principal Investigator must prepare a budget in order to find the funds necessary to do this study. Money is needed to fund the research staff, the data managers, the biostatisticians, prepare all of the documents and pay for the treatments. This study would need hundreds of thousands if not millions of dollars to conduct. There is no place to compromise the budget or the study will not successfully answer the question.

When all of these steps have been completed, and it usually takes a year to do so, enrollment is ready to begin. This is where the patients come in. The patient’s doctor approaches the patient about possible participation. Out of 10 men who will be asked to participate, perhaps four or five will agree and of those, only two or three will complete the study. We have a situation where we don’t know which treatment, radiation or hormonal therapy, is more effective yet most men won’t participate. Why not? Perhaps it is because of the lack of thorough and readily available information; perhaps it is the uncertainty of the drug being evaluated; perhaps it is because many patients are simply being overwhelmed by personal issues in their struggle with prostate cancer.

If we can’t reach our target number of patients within the expected time, the study is likely to collapse. Investigators lose interest, they become involved in other projects, funding is retracted, and the opportunity to answer this question is lost. Unquestionably, patients are needed to participate in well designed trials if we are to adequately study new drugs and/or treatments in a timely manner and bring them into clinical practice.

Perhaps you are such a patient. But before committing, you should thoroughly evaluate the protocols with the help of your doctor. Make sure that a particular trial is appropriate for you and your particular type and stage of disease. Is the potential of the drug or treatment being evaluated likely to be both applicable and important to your situation? Would participation require that you abandon your current treatment program? What are the potential risks? What are the probable side effects? How does your family feel about your participating?

This does not mean that you should automatically reject participating in clinical trials. A particular clinical trial may offer what may be the best available treatment for you and thereby give you the opportunity to receive new, potentially more effective therapy than you are currently receiving. In such a case, participation in the right trial can be important to you personally as well as to other prostate cancer patients. Choosing the right trial for you is yet another part of self-empowerment in combating your disease.

Visit the PC Clinical Trials page at www.prostate-cancer.org for more information.